Background The metabolic syndrome, a cluster of abdominal obesity, dyslipidemia, hypertension and hyperglycemia, is a common basis for atherosclerotic vascular diseases in industrial countries exposed to overnutrition. Adiponectin is an adipose-derived plasma protein with anti-atherogenic and insulin-sensitizing activities. Methods and Results A total of 661 Japanese adults (479 men, 53±10 years; 182 women 56±10 years) were enrolled. Plasma adiponectin concentrations correlated negatively with waist circumference, visceral fat area, serum triglyceride concentration, fasting plasma glucose, fasting plasma insulin, and systolic and diastolic blood pressure in both sexes. A positive correlation was found between plasma adiponectin and high-density lipoprotein cholesterol concentrations in both sexes. The mean number of components of the metabolic syndrome increased as the plasma adiponectin concentration decreased: 2.57±1.34 for men and 2.00±1.51 for women with adiponectin concentrations <4.0 μg/ml. In all, 52.3% of men and 37.5% of women with adiponectin concentrations <4.0 μg/ml fulfilled the criteria for metabolic syndrome. Conclusion Hypoadiponectinemia is closely associated with the clinical phenotype of the metabolic syndrome and measuring the plasma concentration of adiponectin may be useful for management of the metabolic syndrome. (Circ J 2004; 68: 975 - 981)

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Background The relationship between abdominal visceral fat accumulation and lacunar infarcts has not been previously investigated in Japanese men. Methods and Results The subjects were 637 middle-aged (40-64 years) and 222 elderly (65-79 years) men who participated in a health checkup program from 1999 to 2003. The association between lacunar infarcts identified by magnetic resonance imaging and cardiovascular risk factors, including abdominal visceral fat accumulation evaluated by computed tomography, was examined. The prevalence of lacunar infarcts was 4.9%. Hypertension was associated with lacunar infarcts among both the middle-aged men [age-adjusted odds ratio (OR)=2.9 (95% confidence interval (CI): 1.1-7.8)] and the elderly men [OR=5.1 (95%CI: 1.4-19.0)]. Abdominal visceral fat accumulation was slightly associated with lacunar infarcts among middle-aged men, but not among elderly men: OR in the highest (≥117 cm²) vs lowest (≤83 cm²) tertiles of fat area was 2.6 (95%CI: 0.9-7.6) for middle-aged men. Extreme accumulation of visceral fat (≥143 cm²) was still slightly associated with lacunar infarcts after adjustment for age, hypertension, drinking and smoking among middle-aged men [OR=2.7 (95%CI: 0.8-9.1)]. Conclusions This cross-sectional study suggests that abdominal visceral fat accumulation is a possible risk factor of lacunar infarcts, in addition to hypertension, in middle-aged Japanese men. (Circ J 2004; 68: 982 - 987)

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Background Acute massive or submassive pulmonary embolism (PE) has high mortality, but the clinical course according to the location of onset (ie, in-hospital or out-of-hospital) is unknown. Methods and Results In the present study 56 consecutive patients with acute massive or submassive PE were studied retrospectively and a comparison made of the clinical characteristics, and outcomes between in-hospital onset (Group A) and out-of-hospital onset (Group B). Patients in Group A (n=28) had more frequent comorbidities with hemodynamic instability (54% vs 4%, p<0.0001) and temporary risk factors (93% vs 11%, p<0.0001), whereas patients in Group B (n=28) had a longer duration of symptoms (median: 5.5 days vs 0.5 day; p<0.0001), and had higher systolic pulmonary artery pressure (63±17 mmHg vs 46±12 mmHg, p=0.0006). Although in-hospital mortality did not differ between the 2 groups, the recurrence rate was higher in Group B (23% vs 0%, p=0.03). Conclusions Patients who had in-hospital onset of PE had mostly temporary risk factors, unstable hemodynamics and a lower recurrence rate compared with the cases of out-of-hospital onset. In cases of in-hospital onset, prompt diagnosis and suitable treatment is needed to prevent fatalities and cases of out-of-hospital onset should be followed carefully for recurrence. (Circ J 2004; 68: 988 - 992)

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Background Although the development of a coronary guidewire mounted with a pressure sensor has facilitated the measurement of pressure-derived fractional flow reserve (FFR) to assess the functional severity of coronary artery stenoses, the theoretical limitations include diabetes mellitus because of the associated microvascular abnormalities. Methods and Results In the present study 304 vessels and their coronary territories in 96 diabetic and 149 nondiabetic patients were evaluated by pressure-derived FFR and thallium-201 single photon emission computed tomography (SPECT) to determine the applicability of measuring FFR in diabetic subjects. The best cut-off value for FFR to detect myocardial ischemia, as demonstrated by ²⁰¹Tl SPECT, was 0.725 in the diabetic and 0.745 in the nondiabetic patients. Sensitivity and specificity were similar for the 2 groups (83% and 75% (diabetic) vs 79% and 83%). However, diabetic patients with homoglobin (Hb) A_1c ≥7.0% showed lower specificity in comparison with those having HbA_1c <7.0% (64 vs 88%; p=0.045); however, sensitivities were similar (83 vs 83%; p=NS). Conclusions The cut-off value of 0.75 for FFR can detect myocardial ischemia in diabetic patients, although the adequacy of glycemic control should be taken into consideration when assessing the FFR measurements. (Circ J 2004; 68: 993 - 998)

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Background This study was designed to investigate the factors predicting maintenance of sinus rhythm (SR) in patients with chronic atrial fibrillation (AF) undergoing cryoablation of the pulmonary veins (PV-cryo) during cardiac surgery. Methods and Results Seventy-seven patients with AF undergoing PV-cryo were recruited and divided into 2 groups based on whether they were able to maintain SR at discharge. The duration of AF (AF-D), left atrial dimension (LAd), and the average of the peak left atrial appendage outflow velocities (LAA-V) before surgery were determined for both groups. Group SR consisted of 54 patients (70%), and group AF consisted of 23 patients (30%). All patients with an AF-D ≤3 years, LAd <45 mm and LAA-V >40 cm/s were in group SR and all those with an AF-D >10 years and LAd ≥65 mm were in group AF. Only 71% of patients with a LAA-V ≤20 cm/s were in group AF. Conclusions Restoration of AF to SR by PV-cryo can be predicted from a knowledge of the AF-D, LAd and LAA-V. (Circ J 2004; 68: 999 - 1003)

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Background The angiographically no-reflow phenomenon after percutaneous coronary intervention (PCI) predicts poor left ventricular (LV) functional recovery and a high risk of cardiac events in patients with their first acute myocardial infarction (AMI). However, risk factors of long-term adverse outcome for patients with angiographically successful reflow (TIMI (Thrombolysis in Myocardial Infarction) flow grade 3) for the AMI remain unknown. Methods and Results Of 168 echocardiograms were performed before PCI and at discharge, 113 were suitable for analysis. Clinical, angiographic, and echocardiographic variables were submitted to statistical analysis to detect the risk factors of cardiac events. During the follow-up period of 46±20 months, 31 patients had cardiac events, though there were no cardiac deaths. The 2 most important risk factors for congestive heart failure (CHF) or total cardiac events were LV dilation (chi-square: 7.5 and 9.4; both p<0.01) and pseudonormal transmitral flow pattern (PN, chi-square: 4.9, p<0.05 and 6.7, p<0.01, respectively). However, only multivessel disease (chi-square: 9.4, p=0.05) became the predictor for revascularization after PCI. The incidence of CHF or total cardiac events in patients with PN and LV dilation at discharge determined by the Kaplan-Meier method were significantly higher than those with normal or abnormal relaxation transmitral flow pattern (log-rank: 41 and 27, both p<0.001) and no LV dilation (log-rank: 20 and 20, both p<0.001). Conclusion Poor LV diastolic function and LV dilation at discharge are predictors of the cardiac events in patients in whom epicardial coronary flow was well-restored after PCI for the first AMI. (Circ J 2004; 68: 1004 - 1010)

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Background Detailed epidemiological investigations on the relationship of environmental factors, especially occupational and microbiological factors, to the development of idiopathic dilated cardiomyopathy (IDC) are scarce. Methods and Results A multi-hospital case - control study was conducted in 38 hospitals throughout Japan in order to survey IDC cases and age, sex-matched outpatient controls at each hospital. Crude and adjusted odds ratios (ORs) by various environmental factors were calculated in 135 pairs of cases and controls. Univariate analyses revealed significantly increased ORs for lower education, passive smoking in the workplace, cold and/or hot workplace, symptoms of fatigue and history of bacterial infection; in contrast, decreased ORs were associated with a history of rubella and gastroduodenal diseases. Based on multivariate adjusted analyses, lower education (OR 1.96, 95% confidence interval (CI) 1.13-3.40), cold or hot workplace (OR 1.84, 95%CI 1.08-3.12) and history of measles (OR 1.78, 95%CI 1.01-3.08) exhibited a significant positive relationship with IDC risk. History of rubella (OR 0.17, 95%CI 0.06-0.52) and gastroduodenal diseases (OR 0.14, 95%CI 0.07-0.29) were inversely related to the risk. Conclusions Some occupational and microbiological factors appear to relate independently to the development of IDC and further investigation is required to establish their respective mechanisms. (Circ J 2004; 68: 1011 - 1017)

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Background The significance of higher intercostal space electrocardiography (HICS ECG) for the detection of the Brugada sign was investigated. Methods and Results The subjects consisted of 113 cases (108 males, 5 females; mean age, 57±17 years) with incomplete right bundle branch block type QRS morphology and ST-segment elevation (>0.10 mV) in the right precordial leads. Obvious structural heart disease was not observed in any of the subjects. The V_1-3 leads of the standard 12-lead ECG and the HICS ECG were recorded in the supine position, and the amplitude of the terminal portion of the QRS (J-point) and ST-segment (80 ms from the J-point) were measured. In the HICS ECG, there was an increase in the area in which the Brugada sign was detectable (47 leads to 66 leads), and in cases with the Brugada sign, the amplitude of the J-point increased. Conclusions The HICS ECG may be helpful for the detection of the Brugada sign. (Circ J 2004; 68: 1018 - 1022)

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Background The incidence of missed diagnoses of acute cardiac ischemia in the emergency department could be reduced by a new imaging modality. In the present study, the clinical significance of ^99mTc-pyrophosphate (PYP), ¹²³I-β-methyl-p-iodephenyl-pentadecanoic acid (BMIPP), ²⁰¹TlCl scintigraphy (imaging) and T2-weighted inversion - recovery magnetic resonance imaging (MRI) for the detection of culprit lesion in patients with acute coronary syndromes (ACS) was compared. Methods and Results The study group comprised 18 patients with ACS: 12 patients with acute myocardial infarction (AMI) (11 males; mean age, 63±11 years) and 6 patients with unstable angina (UA) (3 males, mean age, 67±5 years). Of the 12 patients with AMI, 10 underwent ²⁰¹TlCl and PYP single photon emission computed tomography (SPECT) studies as a dual-energy acquisition (²⁰¹TlCl/PYP) and 8 underwent ²⁰¹TlCl SPECT within 1 week of the BMIPP study. All 18 patients underwent BMIPP SPECT and MRI. The MRI pulse sequence was black blood turbo short-inversion-time inversion recovery (STIR) (breath-hold T2-weighted studies). The T2-weighted inversion-recovery MRI showed higher sensitivity and negative predictive value than PYP and ²⁰¹TlCl, and higher specificity and positive predictive value than BMIPP and ²⁰¹TlCl. The area under the receiver-operating characteristic curve for PYP, BMIPP, ²⁰¹TlCl and MRI was 0.787, 0.725, 0.731 and 0.878, respectively. The difference between the areas of MRI and BMIPP was significant (p<0.05). Conclusion Accurate detection of culprit lesion is improved by using MRI rather than BMIPP, particularly for patients with ACS. (Circ J 2004; 68: 1023 - 1029)

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Background The hemodynamic effects of enhanced external counterpulsation (EECP) and its mechanism(s) were investigated in relation to neurohumoral factors in patients with acute myocardial infarction (AMI). Methods and Results Twenty-four patients with AMI were studied before, during and after EECP treatment for 60 min. Heart rate (HR), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were determined. In addition, circulating concentrations of neurohumoral factors were determined at each time point. HR did not change following EECP treatment. However, RAP and PCWP increased significantly and CI was significantly elevated during EECP and thereafter. Blood atrial natriuretic peptide (ANP) concentration was significantly increased 15 and 60 min after the start of EECP treatment, but brain natriuretic peptide (BNP) did not change. Renin, aldosterone and catecholamine concentrations also did not change. Conclusion Treatment with EECP resulted in an increased preload because of increased venous return, and CI was increased thereafter. In patients with AMI, EECP increased blood ANP concentration, but not BNP, which suggests that an increase in ANP without an increase in BNP is an important mechanism for the effects of EECP treatment. (Circ J 2004; 68: 1030 - 1034)

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Background The effect of calcium antagonists on regional left ventricular (LV) filling dynamics in patients with hypertrophic cardiomyopathy (HCM) is not well known, so the present study evaluated the results of echocardiography with color kinesis (CK) analysis during diltiazem infusion. Methods and Results Nineteen patients (16 men, 3 women; mean age 55±15 years) underwent echocardiography with CK analysis during intravenous diltiazem (10 mg/2 min). Using the quantitative CK software the LV short-axis image was divided into 6 segments and the percent endocardial expansion at the early, mid- and late-diastolic filling time was averaged for all segments, with the standard deviation of the mean used as an index of diastolic asynchrony (asynchrony index). The regional mean filling time was also measured for the corresponding segments. As global diastolic parameters, the global filling time, peak filling rate, and the time-to-peak filling were calculated. After the administration of diltiazem, the asynchrony index was decreased for all three diastolic filling times. Diltiazem shortened the mean filling time overall, especially in the posterior and lateral wall segments. These findings were associated with significant improvement in the CK-derived global diastolic parameters. Conclusions Diltiazam has a favorable effect on LV diastolic asynchrony, which may account for the acute changes in global LV relaxation. (Circ J 2004; 68: 1035 - 1040)

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Background It remains controversial whether prophylactic anticoagulation for embolism is required in patients with atrial flutter (AFL) prior to and following cardioversion as in patients with atrial fibrillation. To evaluate the potential prothrombotic state following cardioversion of AFL, concentrations of hemostatic markers were determined before and after conversion to sinus rhythm (SR). Methods and Results In 12 patients (mean age 68 years) with AFL who underwent transesophageal echocardiography in the plasma concentrations of markers for platelet activity (platelet factor 4 (PF4) and β-thromboglobulin (β-TG)), thrombotic status (thrombin-antithrombin III complex (TAT) and prothrombin fragments 1 and 2 (F1+2)) and fibrinolytic status (D-dimer and plasmin-α₂-plasmin inhibitor complex (PIC)) were determined during AFL, and 3 days and 7 days after restoration of SR. Left atrial appendage (LAA) blood flow velocity was lower immediately after than before restoration of SR (29±11 vs 41±23 cm/s, p<0.05). Three patients developed left atrial spontaneous echo contrast immediately after restoration of SR. Although the concentrations of the markers of platelet activity did not change after restoration of SR, those of TAT and PIC increased 7 days after restoration of SR as compared with during AFL (p<0.05). Conclusions AFL patients have a potential risk for thromboembolism after restoration of SR and therefore anticoagulation might be required in selected patients. (Circ J 2004; 68: 1041 - 1044)

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Background Multislice computed tomography (MSCT) was used to evaluate coronary artery remodeling in patients with acute coronary syndrome (ACS) and stable angina (SA). Methods and Results MSCT was performed in 31 patients with ACS and 26 patients with SA and intravascular ultrasound (IVUS) was performed in 28 of these 57 patients. In both the MSCT and IVUS analyses, coronary artery remodeling was assessed by the remodeling index (RI): RI >1.10 was defined as positive coronary artery remodeling (PCAR) and RI <0.95 was defined as negative coronary artery remodeling (NCAR). The RI assessed by MSCT closely correlated with that of IVUS (r=0.86, n=28). The vessel area at the region of maximum luminal narrowing was also comparable between the MSCT and IVUS measurements (r=0.92). PCAR was present in 19 patients (61.3%) with ACS, but in none of the patients with SA (p<0.0001). However, NCAR was present in only 1 patient with ACS (3.2%), but was present in 18 patients (62.9%) with SA. The RI was significantly larger in patients with ACS (1.19±0.18) than in those with SA (0.89±0.10, p<0.0001). Conclusion MSCT accurately assesses coronary artery remodeling. (Circ J 2004; 68: 1045 - 1050)

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Background The relationship between enhanced myocardial oxidative stress and impaired β-adrenergic signaling remains to be characterized during the development of dilated cardiomyopathy. Methods and Results Alterations in myocardial oxidative stress and β-adrenergic signaling, as well as left ventricular (LV) functional and structural changes, were evaluated during the development of cardiomyopathy in TO-2 hamsters; F1B hamsters served as controls. LV dysfunction was first apparent at 8 weeks of age and deteriorated thereafter in the TO-2 hamsters. At 32 weeks, the animals exhibited heart failure with an increased plasma norepinephrine concentration. Cardiac myolysis, as demonstrated by elevated plasma concentration of cardiac troponin T, peaked at 8 weeks. The glutathione redox ratio revealed increased oxidative stress in the LV myocardium in TO-2 hamsters even at 4 weeks and became manifest after 8 weeks. The hearts of TO-2 hamsters had significantly reduced superoxide dismutase activity from 8 weeks onward compared with control hamsters. However, glutathione peroxidase activity was unchanged at any time point. The LV functional response to isoproterenol was markedly reduced at 8 weeks, without any apparent changes in the amount of β-adrenergic signaling molecules, and it deteriorated thereafter. Adenylyl cyclase activity was significantly decreased, despite increased amounts of both G_s α mRNA and protein, in the LV myocardium at 18 weeks. Conclusions Myocardial oxidative stress is actually enhanced in the initial development of LV dysfunction. Both activation of myocardial oxidative stress and impairment of β-adrenergic signaling become prominent at the stage of severe LV dysfunction. Myocardial oxidative stress may be involved in the development of β-adrenergic desensitization. (Circ J 2004; 68: 1051 - 1060)

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Background The effect of pitavastatin on the mRNA levels of apolipoprotein (apo) A-I, peroxisome proliferator-activated receptor α (PPARα), cholesterol 7α-hydroxylase (CYP7A1), and farnesoid X receptor (FXR) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so, to determine a possible molecular mechanism. Methods and Results HepG2 cells were cultured in serum-free Dulbecco's modified Eagle medium for 18 h before drug treatment. Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription-real time polymerase chain reaction. Pitavastatin at 0.1, 1, 5, and 10 μmol/L increased the mRNA levels of apo A-I, PPARα, CYP7A1, and FXR in a dose-dependent manner. The mRNA levels of apo A-I, PPAR α, CYP7A1, and FXR similarly increased with increasing doses of pitavastatin. Coincubation of mevalonate (4 mmol/L) with pitavastatin (5 μmol/L) reversed the inductive effects of pitavastatin on the mRNA levels of these genes, indicating that the inductive effects of pitavastatin were related to its inhibition of HMG-CoA reductase. Conclusions Pitavastatin increased the mRNA levels of CYP7A1 in HepG2 cells, suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low-density lipoprotein cholesterol-lowering effects. (Circ J 2004; 68: 1061 - 1066)

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Background The vascular NAD(P)H oxidase-derived superoxide anion (O₂-) plays a crucial role in the pathological progression of hypertension and atherosclerosis, and HMG-CoA reductase inhibitors (statins) have vascular antioxidant effects. However, it is unclear whether the vascular NAD(P)H oxidase is involved in the endothelial dysfunction of congestive heart failure (CHF) and whether HMG-CoA reductase inhibitors (statins) exert their vasoprotective effects in CHF. The present study examined both the involvement of vascular NAD(P)H oxidase in endothelial dysfunction in dogs with tachycardia-induced CHF and the therapeutic effect of a statin (pitavastatin). Methods and Results Femoral blood flow (FBF) responses to acetylcholine was significantly impaired in the CHF group, but were improved by pitavastatin. Vascular O₂- production, NAD(P)H oxidase activity and Nox4 and p47phox expression were significantly elevated in CHF compared with the normal group. The elevated O₂-production in the CHF group was suppressed by the NAD(P)H oxidase inhibitor, apocynin, to the normal level. In contrast, neither the gene expression nor the activity of endothelial nitric oxide synthase (eNOS) differed significantly between the normal and CHF groups. However, pitavastatin significantly suppressed O₂- production, NAD(P)H oxidase activity and Nox4 and p47phox expression and increased eNOS expression and activity compared with the CHF group. Conclusions The activated vascular NAD(P)H oxidase contributes to endothelial dysfunction in CHF, which was partly improved by pitavastatin via its inhibition of NAD(P)H oxidase. (Circ J 2004; 68: 1067 - 1075)

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An 84-year-old woman was admitted to hospital with chest pain at rest. An electrocardiogram showed ST-segment elevation in leads II, III, aV_F and V_2-6, and the 2-dimension echocardiogram showed apical ballooning akinesis and basal hyperkinesis of both ventricles. ^99mTc-tetrofosmin myocardial single photon emission computed tomography (SPECT) showed severely reduced uptake in the apex. Coronary angiography did not show any organic stenosis, and epicardial coronary spasm was not provoked by the ergonovine loading test. Left ventriculography showed apical ballooning akinesis and basal hyperkinesis, which were also apparent on right ventriculography. The coronary flow velocity pattern showed rapid diastolic acceleration and deceleration times, and the coronary flow reserve measured with a Doppler guide wire was severely decreased. ^99mTc-tetrofosmin myocardial SPECT showed improvement in the findings after 14 days, and the coronary flow velocity pattern and coronary flow reserve improved after 30 days. Left and right ventriculography both revealed mild improvement in the wall motion. These findings suggested that a microcirculation disturbance caused ampulla (`Takotsubo') cardiomyopathy. (Circ J 2004; 68: 1076 - 1080)

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A 44-year-old woman had tako-tsubo-like ventricular dysfunction with chest pain and ST segment elevation on the ECG. Echocardiography revealed a bicuspid aortic valve with moderate to severe aortic regurgitation. She developed mild heart failure during the clinical course, but the medication (furosemide, enalapril, and asprin) had to be stopped because of skin eruptions. Four weeks after ceasing the antiplatelet agent, she was re-admitted with acute renal infarction. Enhanced chest computed tomography revealed a filling defect in the left ventricle and echocardiography showed a high echogenic mass in the left ventricular apical wall. These findings strongly suggested that the renal infarction was caused by an embolism derived from a left ventricular thrombus that formed during the clinical course of the transient left ventricular apical ballooning. Anticoagulation therapy with urokinase and warfarin successfully lysed the thrombus. Left ventricular thrombus should be considered a complication of transient left ventricular apical ballooning, especially in patients with organic heart disease. (Circ J 2004; 68: 1081 - 1083)

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Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as β-blockers, are more effective for relief of RVOTO. (Circ J 2004; 68: 1084 - 1087)

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The experience of using a novel application of intravascular ultrasound (IVUS)-guided percutaneous coronary interventions for chronic total occlusions is reported in 2 cases. In the first case, an IVUS catheter was advanced into a side branch to identify the entry point of the major branch. In the second case, IVUS-guided penetration of the guidewire from the false lumen to the true lumen after causing a dissection was successful. (Circ J 2004; 68: 1088 - 1092)

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